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Estrogen and Alzheimer Disease: Is It Really All in the Timing?
There is a wealth of evidence, including this latest study, suggesting the involvement of sex steroids in the etiology of Alzheimer disease (AD) (reviewed in Manly et al., 2000; Casadesus et al., 2004; Casadesus et al., 2005) and data indicating a positive effect of hormone replacement therapy (HRT, Henderson et al., 1994; Kawas et al., 1997).

However, contradicting findings from the Women's Health Initiative Memory Study, reporting negative cognitive effects following HRT in women at an AD-vulnerable age (Henderson et al., 2003; Rapp et al., 2003; Shumaker et al., 2003; Almeida et al., 2006) have caused complete havoc in the estrogen research field and cast serious doubt on the role of sex steroid hormones in age-related cognitive decline, neuronal dysfunction, and AD etiology. One key issue that these seemingly opposing studies lead to is the importance of the timing of estrogen treatment. However, other alternative explanations are equally, if not more, plausible. Indeed, one must not forget that estrogen is part of a hormonal axis and thus does not work alone.

In this regard, a more encompassing hypothesis for the timing effects of HRT is that degenerating dynamics within the hypothalamic-pituitary-gonadal (HPG)-axis observed during and after the menopausal years, specifically the capacity of estrogen to suppress rising levels of the gonadotropin luteinizing hormone (LH), is a key element in AD-related cognitive/neuronal function decline. In support of this, estrogen-feedback on LH secretion (Lloyd et al., 1994) and GnRH gene expression (Park et al., 1990) is decreased during aging. Estrogen also becomes increasingly less effective at modulating LH expression and biosynthesis the later HRT is started after ovariectomy (OVX, King et al., 1987). These later findings parallel those for cognitive decline after menopause and OVX, such that HRT begun a long interval after menopause or OVX fails to rescue cognitive/neuronal function associated with these events (reviewed in Gibbs, 2000; Sherwin, 2005; Daniel et al., 2006). Also of note is the fact that LH receptors are present in the highest levels in the hippocampus (Lei et al., 1993), a major cognition center; ICV treatment with hCG has behavior modulatory effects (Lukacs et al., 1995). Aged transgenic AD mice (Tg 2576) treated with leuprolide acetate, a GnRH agonist that depletes levels of gonadotropins and sex steroids via the internalization of the GnRH receptor, showed sustained cognitive function compared to non-treated animals (Casadesus et al., 2006). In clinical trials, luprolide acetate appears to also benefit patients with AD (see publications list of sponsoring company).

Timing certainly plays a role, but a question that is also worth asking is whether estrogen is the single bright star that it has been reputed to be until now or simply one of the stars of a well-organized team (Webber et al., 2005).